Our Program Project is focused on the genetic dissection of metabolic syndrome (MetSyn) in both mouse models and human populations. Our approach is, we believe, unique in its multifaceted and integrative approaches. These include a combination of genetic, genomic, biochemical, physiologic, and bioinformatic analyses. During the current grant cycle, each of the four projects has been highly productive. Project 1 has utilized traditional positional cloning as well as integrative genetics in mice to identify several novel genes affecting adiposity, lipoprotein metabolism, and insulin sensitivity. Project 2 has used linkage and association analysis of human populations to identify a number of novel genes in triglyceride and HDL metabolism. Project 3 has identified and characterized a novel gene controlling the maturation of lipases. Project 4 has carried out detailed molecular studies of the lipin family of proteins, identifying key functions in fat storage and insulin sensitivity. We now propose 4 Projects and 4 Cores. All projects are direct continuations of the present projects, as are the 4 Cores. Project 1 will focus on the integration of mouse and human gene networks for MetSyn and also address the problem of gene-by-environment interactions in MetSyn. Project 2 will further elucidate underlying mechanisms for novel genes identified in human subjects during the present cycle and use both linkage and association in large population samples to further dissect the genetic factors contributing to MetSyn. Project 3 will focus on the biology lipase maturation factor-1, in both mice and humans. Project 4 will examine the role of lipins in adipogenesis and insulin sensitivity and in statin-induced myopathy as well as new genes identified in Project 1. Each of the proposed Projects will interact significantly with each of the other Projects and all of the Cores.